The objective of this research is to determine the influence of cardiovascular dynamics on the biological disposition of intravenously administered anesthetic agents, including the thiobarbiturates, narcotic analgesics, ketamine, and neuromuscular blocking drugs. All of these drugs are widely used along with nitrous oxide to produce general anesthesia, especially for patients with cardiovascular instability (e.g., cardiac disease, hypovolemia, shock). It is a widely held clinical impression that such patients are more susceptible than normal subjects to the actions of these drugs. Their greater susceptibility could result in part from alterations in their cardiovascular dynamics which determine the delivery of drugs to sites of action, storage, metabolism and excretion. We are investigatigating the pharmacokinetics of the above mentioned drugs in both animals and man under normal and abnormal conditions of cardiovascular function. Hypotension, hypovolemia, hypoproteinemia, hemodilution and hypothermia are produced deliberately in selected patients for surgical purposes. For example, deliberate hypotension is used to decrease blood loss and to facilitate certain types of plastic surgery. Such clinical circumstances offer an opportunity to investigate the influence of altered cardiovascular dynamics on the disposition of anesthetic drugs in human subjects under controlled conditions. Similar conditions can be created in experimental animals for more detailed studies. Sensitive and specific analysis of intravenously administered anesthetic drugs in biological specimens will include solvent extraction procedures in combination with spectrophotofluorometry, gas chromatography, radioimmunoassay and other radioisotopic techniques. Measurements of cardiovascular function will include systemic arterial, central venous, pulmonary arterial and capillary wedge pressures, cardiac output and circulating blood volume. Experimental and clinical conditions will be controlled in terms of blood gases, pH, electrolytes and protein content of blood.